DermaXon?s project goal is to develop efficacious novel selective inhibitors of CYP26A1 for the topical treatment of ichthyosis. Congenital ichthyosis is a family of hereditary disorders of keratinization characterized by dry, scaling skin that may be thickened or very thin, impacting the quality of life of patients and their family members. Currently, there is no cure for ichthyosis and available medicines are aimed only at moisturizing and exfoliating to reduce dryness, scaling and cracking of skin. Retinoic acid (RA) derivatives are known to normalize abnormal differentiation of keratinocytes and have keratolytic effects that mitigate hyperkeratosis in patients with ichthyosis. However, RA has poor pharmacokinetics in humans because it induces its own clearance by upregulating metabolic enzymes and its use is limited due to mucocutaneous side-effects, abnormalities of serum lipid profiles, bone spurs and hair loss. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26) of which there are three isoforms: CYP26A1, CYP26B1 and CYP26C1. For the first time, DermaXon has shown that CYP26A1 is the isoform responsible for RA metabolism in human skin. Currently approved topical RAR?/?-selective retinoids, whose effects are mediated by direct receptors activation, are also potent non-selective inhibitors of both CYP26A1 and B1, which likely explains their adverse side effects including retinoid dermatitis. In this STTR, DermaXon will demonstrate that selective inhibition of CYP26A1 will increase RA concentration in ichthyotic skin, resulting in normalization of keratinocyte differentiation and mitigating hyperkeratosis associated with ichthyosis. This approach will provide a therapeutic advantage in ichthyosis without side effects associated with non-specific inhibition of other CYP26s. We are the only group world-wide to have developed selective nanomolar CYP26A1 inhibitors, providing a new therapeutic class against ichthyosis. These inhibitors shown to be highly selective for CYP26A1, avoid the adverse effects induced by non-targeted P450 inhibition associated with previously described non-specific azole-containing CYP26 inhibitors, such as liarozole. We are uniquely suited to demonstrate the utility of CYP26A1 as a therapeutic target as we bring together the expertise of academic-industry partnerships between DermaXon (expert in drug discovery and formulation) and Northwestern University (Dr. Paller, expert in ichthyosis). In this proposed award period, DermaXon will complete the characterization of the previously developed lead candidate structures which are highly potent and selective CYP26A1 inhibitors. The effects of these CYP26A1 inhibitors will be assessed and compared to the effects of a dual CYP26A1/B1 inhibitor and a selective CYP26B1 inhibitor at increasing RA concentration in keratinocytes isolated from patients with ichthyosis, and in a human epidermis model of ichthyosis. By the end of this project, DermaXon will have identified a potent, selective, topically active, safe and efficacious CYP26 inhibitor that can treat keratinization disorders in preclinical skin models of ichthyosis and, ready for IND-enabling formal studies to address the therapeutic needs in ichthyosis.